1,2-METHYLENE-17.alpha.-ACYLOXY(OR IMPROVED HYDROXY)-9.beta.,10.alpha.-STEROID COMPOUNDS OF THE PREGNANE SERIES, PHARMACEUTIC PREPARATIONS OF THE BASIS OF THE NOVEL COMPOUNDS AND METHODS OF PRODUCING SAID COMPOUNDS AND PREPARATIONS

摘要

1330563 1#,2# - Methylene - 9#,10 - steroids PHILIPS GLOEILAMPENFABRIEKEN NV 19 April 1971 [4 March 1970] 22847/71 Heading C2U [Also in Division A5] The invention comprises compounds of formula wherein X is H and Y is free or esterified hydroxy, or X+Y is oxo; R 3 is a 3-oxo-#SP4/SP, 3- oxo-#SP4,6/SP, 3-ORSP1/SP-#SP3,5/SP, 3-ORSP1/SP-#SP4,6/SP or 3#-ORSP1/SP- #SP4,6/SP system (where ORSP1/SP is an esterified or etherified hydroxy group); R 6 is H, Cl, F, Me, 6,6-difluoro or 6,6-dichloro with the proviso that when R 6 is H then R 7 is 6#,7#-methylene; R 7 is a 7-hydrogen atom or a 6#,7#-methylene group with the proviso that when R 7 is a 6#,7#- methylene group then R 6 is H, F or Cl and R 3 is a 3-oxo-#SP4/SP system; R 13 is Me or Et; R 17 is C 1-5 etherified hydroxy or C 1-8 esterified hydroxy; and R 21 is H, F or free or esterified hydroxy. Compounds I are prepared (i) by esterifying or etherifying the corresponding 17-(free hydroxy) compounds (wherein R 3 is 3-oxo-#SP4/SP or 3-oxo-#SP4,6/SP); (ii) by esterifying or etherifying the corresponding 3-(free hydroxy)-#SP4,6/SP compounds; (iii) by halogenating the corresponding #SP3,5/SP-3- ORSP1/SP-6-unsubstituted compounds to give #SP4/SP-3- oxo-6-(fluoro or chloro) compounds; (iv) by converting the corresponding 21-iodo compounds (wherein R 3 is 3-oxo-#SP4/SP) either into 21- fluoro compounds using AgF preferably in the presence of CaF 2 , or into 21-acetoxy compounds using triethylaminoacetic acid and an alkali metal acetate; (v) by catalytic hydrogenation of the corresponding 6-methylene, 6-dichloromethylene or 6-dibromomethylene compounds (wherein R 3 is 3-oxo-#SP4/SP) into 6-methyl compounds ; (vi) by isomerization of the corresponding #SP4/SP-3-oxo-6-methylene compounds into #SP4,6/SP- 3-oxo-6-methyl compounds under palladium catalysis; and (vii) by dehydration of the corresponding #SP4/SP-3-oxo-6-halo-7-hydroxy compounds into #SP4,6/SP-3-oxo-6-halo compounds. Compounds I are interconverted by (i) 20/21- esterification/de-esterification; (ii) 3-enol esterification/enol etherification; (iii) reduction of 20-oxo to hydroxy; (iv) 6,7-hydrogenation/ dehydrogenation; (v) 6-dihalogenation; and (vi) 6,7-methylenation. 1#,2# - Methylene - 6# - chloro - 7# - hydroxy- 17 - acetoxy - 9#,10 - pregn - 4 - ene - 3,20 - dione is prepared from 1#,2# - methylene - 17 - acetoxy - 9#,10 - pregna - 4,6 - diene - 3,20 - dione by reaction with chromyl chloride. 1#,2#; 6#,7# - Bismethylene - 6 - chloro - 17- hydroxy - 9#,10 - pregn - 4 - ene - 3,20 - dione is prepared from 1#,2#-methylene-6-chloro-17- acetoxy - 9#,10 - pregna - 4,6 - diene - 3,20- dione via 1#,2# - methylene - 6 - chloro - 17- hydroxy - 9#,10 - pregna - 4,6 - diene - 3,20- dione. 1#,2# - Methylene - 6 - methyl - 17 -hydroxy - 9#, 10 - pregna - 4,6 - diene - 3,20 - dione (1V) is prepared from 17 - hydroxy - 9#,10 - pregna: 1,4,6,triene-3,20-dione (I) by the sequence, I -# 1#,2# - methylene - 17 - hydroxy - 9#- 10 - pregna - 4,6 - diene - 3,20 - dione (II) -# 1#,2# - methylene - 17 - hydroxy - 9#,10 - pregn- 4 - ene - 3,20 - dione (III) -# 1#,2# - methylene- 6# - trichloromethyl - 17 - hydroxy - 9#,10- pregn-4-ene - 3,20 - dione -# 1#,2#; 6 - bismethylene - 17 - hydroxy - 9#,10 - pregn - 4 - ene- 3,20-dione -# IV. 1#,2#; 6#,7# - Bismethylene - 17 - hydroxy- 9#,10 - pregn - 4 - ene - 3,20 - dione is prepared from II by reaction with dimethylsulphoxonium methylide. 1#,2# - Methylene - 3,17 - diacetoxy - 9#,10- pregna-3,5-dien-20-one is prepared from III by reaction with Ac 2 O. 1#,2# - Methylene - 6 - fluoro - 17 - hydroxy- 9#,10 - pregna - 4,6 - diene - 3,20 - dione is prepared by hydrolysis of the 17-acetate thereof. 1#,2# - Methylene - 3 - hydroxy - 6 - chloro- 17 - acetoxy - 9#,10 - pregna - 4,6 - dien - 20- one is prepared by NaBH 4 reduction of the corresponding 3,20-dione.